Method of treatment of nervous tensions in mammals with certain substituted indoles and indolines



United States Patent 3,496,275 METHOD OF TREATMENT OF NERVOUS TEN- SIONS IN MAMMALS WITH CERTAIN SUBSTI- TUTED INDOLES AND INDOLINES Michel Leon Thominet, Paris, France, assignor to Socit dEtudes Scientifiques et Industrielles de lIle-de-France, Paris, France No Drawing. Continuation-impart of application Ser. No. 669,297, Sept. 20, 1967. This application Aug. 8, 1968, Ser. No. 751,045

Claims priority, application France, July 25, 1961, 869,013, 869,014 Int. Cl. A61k 27/00 US. Cl. 424274 6 Claims ABSTRACT OF THE DISCLOSURE Nervous tension in mammals is significantly lessened by the administration of certain substituted indoles and indolines. Treatment may be given orally or parenterally.

This application is a continuation-in-part of application Ser. No. 669,297, filed Sept. 20, 1967, now US. Patent No. 3.4131934. The application S.N. 669,297 was a continuation-in-part application of an application S.N. 466,070, filed June 15, 1965, now abandoned, and this latter application was a divisional application of US. patent application S.N. 210,555, filed July 17, 1962, now US. Patent No. 3,198,807.

This invention relates to the treatment of emesis or nervous tension in mammals by the administration of substituted carboxamide indoles or the corresponding indolines of such indoles.

The substituted carboxamide indoles utilized in the methods of treatment of this invention have the formula:

in which R, and R are lower alkyl groups, such as the methyl, ethyl, propyl or isopropyl group; W is an alkylene group of 2-4 carbon atoms, such as the ethylene, propylene, methyl ethylene or Z-methyl propylene group; and A is a lower alkoxy group, such as methoxy, ethoxy, isopropoxy or butoxy.

The substituted carboxamide indoles are produced by reacting a lower alkyl ester of 3-hydroxy-2-indolyl formic acid with a lower alkylating agent in acetone in the presence of potassium carbonate treating the resulting reaction product with the required disubstit-uted diamine in boiling toluene, recovering the alcohol formed in the course of the reaction, expelling the solvent, acidifying, reprecipitating the base by adding an alkali to the acid solution and forming a salt of the carboxamide by reacting in an inert solvent an acid with the dissolved base For the hydrochloride, for instance, a stream of gaseous dry hydrogen chloride is caused to pass into an isopropyl alcohol solution of the base.

For example, the reacting of the preparation of the 3-methoxyindole 2 N-(diethylaminoethyl) carboxamide is indicated as follows:

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0 0 H3 heat dicthylimintfethylamine in to uene N C 00 0 H C2H5 CONHCHzCHzN To obtain the corresponding indolines from the substituted carboxamide indoles, hydrogenation is efiectuated in an autoclave under pressure and heat in the presence of a known catalyst such as platinum or palladium carbon in an inert solvent like alcohol. The solvent is expelled after hydrogenation and the residue is recrystallized. Salts of the substituted indoline base may be obtained by treating the base in solution in an inert solvent with the required acid. To obtain the hydrochloride, for example, the base is dissolved in isopropyl alcohol and a current of gaseous dry hydrogen chloride is passed into the alcoholic solution.

The substituted carboxamide indoles, the corresponding indolines and their salts of this invention possess significant pharmacological properties and may be used for the treatment of emesis associated with many conditions, such as pregnancy and seasickness, and behavior disturbances. For this purpose, the substituted indoles, substituted indolines or their salts may be incorporated in or combined with pharmaceutically acceptable carriers.

Examples of the preparation of specific substituted indoles and a correspondin substituted indoline are as follows:

PREPARATION I 3 -methoxyindole-2-N- (diethylaminoethyl) -carboxamide hydrochloride 91 grams of methyl-Z-methoxyindole-2-carboxylate and 103 grams of diethylaminoethylamine are dissolved in cc. of toluene. The solution is heated to boiling, and the methanol formed in the course of the reaction, which requires 22 hours, is removed.

The resulting 3-methoxyindole-2-N-(diethylaminoethyl) carboxamide is dissolved in about 500 cc. of water, is acidified and the aqueous acid solution extracted with ether. The base is precipitated by the addition of ammonia to the acid solution, is filtered and recrystallized in 95% ethanol. There are obtained 102 g. of a bright yellow product having a melting point of 117-118 C The hydrochloride of that base is prepared by dissolvin the base in isopropyl alcohol and passing into that solu tion 13 g. of gaseous dry hydrogen chloride. There are obtained 111 grams of 3-methoxyindole-2-N-(diethylaminoethyl) carboxamide hydrochloride having a melting point of 173-174 C.

PREPARATION II 3-ethoxyindole-2aN- (diethylaminoethyl)-carboxamide hydrochloride 124 grams of ethyl-3-ethoxyindole-Z-carboxylate and 126 grams of diethylarninoethylamine are boiled with.

cc. of Xylene for 22 hours. The alcohol formed in the course of the reaction is removed. The reaction prodnot is dissolved in about 500 cc. of water, acidified, and

the aqueous acid solution is extracted with ether. The base is precipitated by the addition of ammonia. By recrystallization in 95% ethanol, 125 grams of a white product is obtained, having a melting point of 141-142 C.

The hydrochloride of the base is prepared by dissolving this base in isopropyl alcohol and passing through it grams of gaseous dry hydrogen chloride. There are obtained 132 grams of 3-ethoxyindole-2-N(diethylaminoethyl) carboxamide hydrochloride having a melting point of 160161 C.

PREPARATION III 3-ethoxyindoline-2-N' (diethylaminoethyl) carb oxamide hydrochloride CENTRAL DL (mouse) in mg. per kg. of

The methods of this invention are effective in the lessening or removal of nervous tensions. For example, the salt of 3-ethoxyindole-2-N-(diethylaminoethyl) carboxamide and 3-ethoxyindoline-2-N-(diethylaminoethyl) carboxamide have striking antifibrillating characteristics. When compared with procaine amide, 3-ethoXyindole-2-N- (diethyla-minoethyl) carboxamide hydrochloride is about three times more active than procaine amide, While 3- ethoxyindoline-Z-N-(diethylaminoethyl) carboxamide hydrochloride is approximately eight times more active than procaine amide.

The central nervous system depressive properties of the compounds utilized in the methods of this invention is illustrated in the following table giving these properties of the compounds of the three preparations in this application. The table of these properties is as follows:

DEPRESSIVE PROPERTIES OF COMPOUNDS OF PREPARA- TIONS 1, 2 AND 3 Effective doses DL U in mg. per kg. of body weight of preparations 1, 2, and 3 Test 1 2 3 I Entered in mouse 54 1 base. 1 80.

Antimorphine in mouse (suppression of Straub 293 4 Base 236 2 base phenomenon) Action on spontaneous motility in mouse 17.9 1 base- 711 1 base.-- 43.8 1 Base.

1 Intraperitoneally administered. 2 subcutaneously administered. 3 Intravenously administered.

4 Orally administered.

D14 0 in mg. per kg. of body Composition Weight Composition #1, 3anethoxyindole-2-N-(diethylaminoethyl) oarboxamide Composition #2, 3ethoxyindole-2-N carboxazrnide u 37. 5 Composition #3, 3-ethoxyindoline-2-N-(d1ethylammo- 34 ethyl) oarboxamide The following table shows the intraperitoneal and subcutaneous toxicities of such compositions.

The preparations utilized in the methods of this invention or salts thereof, such as the hydrochloride salt, can be administered in the form of:

d (Ia) Sugar coated 25 mg. tablets at the rate of 6 to 8 ar y; a

(b) Injectible ampoules or aqueous solutions for use in aerosol or other sprays in dosages of mg. per 2 cc. of solution at the rate of 2 to 4 doses daily;

d (c) Suppositories of 100 mg. at the rate of 2 to 4 aily;

(d) Granulated sucrose for babies at 10 mg. per dose, equivalent to one full level teaspoon (about 4 g.);

(e) Sugar syrup for babies at a dosage of 10 mg. per teaspoon of 5 cc.

The duration of the treatment and the dosages utilized vary with the illness treated. With mammals having the weight span of man, the desirable daily dosage is in the range of 10 to 800 mg. Such treatment and dosage in a particular situation would be determined by a professional skilled in the art of the prevention, cure and alleviation of disease, illness and injury of mammals.

What is claimed is:

1. The method of treating nervous tensions in mammals, said method comprising administering to a mammal requiring such treatment 1 to 5 mg. per kg. of body weight 5 of said mammal of a compound selected from the group consisting of substituted indole carboxamides, non-toxic acid addition salts of said indole carboxamides, corresponding indoline carboxamides and non-toxic acid addition salts of said corresponding indoline carboxamides, said substituted indoles being of the formula:

in which A is lower alkoxy; W is alkylene of 2-4 carbon atoms; and R and R are lower alkyl.

2. The method in accordance with claim 1, in which the daily dosage is 10 mg. to 800 mg. of the compound.

3. The method in accordance with claim 1, in which a single dosage is 10 mg. to 160 mg. of the compound.

4. The method in accordance with claim 1, in which 20 the compound administered is a non-toxic acid addition 6 salt of 3 methoxyindole 2-N-(diethy1aminoethyl)carboxamide.

5. The method in accordance with claim 1, in which the compound administered is a non-toxic acid addition salt of 3 ethoxy indole 2 N-(diethylamin-oethyl) carboxamide.

6. The method in accordance with claim 1, in which the compound administered is a non-toxic acid addition salt of 3 ethoxyindoline-Z-N-(diethy1aminoethyl)carboxamide.

References Cited UNITED STATES PATENTS 2,691,025 10/1954 Clinton et al. 260-559 2,957,005 10/1960 Coenen et al. 260-319 2,980,692 4/1961 Albertson 260-319 2,986,573 5/1961 Topliss et al. 424-274 3,004,889 10/1961 Kuna et al. 424-274 ALBERT T. MEYERS, Primary Examiner S. I. FRIEDMAN, Assistant Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,496,275 February 17, 1970 Michel Leon Thominet It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 47, "methyl2-methoxyindo1e-2-carboxylate" should read methyl3-meth0xyindo1e2-carboxylate Signed and sealed this 8th day of December 1970.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Commissioner of Patents Edward M. Fletcher, Jr. Attesting Officer 

